Correspondence

Cellulose Sulfate for Prevention of HIV Infection

N Engl J Med 2008; 359:2066-2068November 6, 2008

Article

To the Editor:

The results of the trial of cellulose sulfate as a vaginal gel for the prevention of human immunodeficiency virus (HIV) infection, reported by Van Damme et al. (July 31 issue),1 indicated that cellulose sulfate did not prevent sexual transmission of HIV and may have increased the risk of HIV acquisition, as compared with placebo. The cellulose sulfate and placebo gels had a pH of 7.5 and 4.4, respectively. The healthy human vagina provides a low pH, diminishing HIV infectivity and transmission of cell-associated HIV.2,3 Therefore, microbicides should have a pH of approximately 4.5.3 The apparently increased risk of HIV acquisition among women using the cellulose sulfate gel might be due to the disparity in pH between the active-treatment and placebo gels.

The anti-HIV activity of anionic polymers (including cellulose sulfate) may be compromised by seminal fluid.4 This is expected to be overcome by inclusion of acidic pH buffering systems.4 Such combinations are currently in the microbicide pipeline. Langerhans' cells first encounter HIV during sexual transmission of the virus and bind HIV by means of langerin. Captured virus is internalized and degraded.5 It remains to be established whether candidate microbicides interfere with this defense mechanism and possibly increase the probability of HIV acquisition.

A. Robert Neurath, Ph.D.
Virotech, New York, NY 10003
arneurath@att.net

5 References

1. 1

   Van Damme L, Govinden R, Mirembe FM, et al. Lack of effectiveness of cellulose sulfate gel for the prevention of vaginal HIV transmission. N Engl J Med 2008;359:463-472[Erratum, N Engl J Med 2008;359:877.]
   Full Text | Web of Science | Medline

2. 2

   Olmsted SS, Khanna KV, Ng EM, et al. Low pH immobilizes and kills human leucocytes and prevents transmission of cell-associated HIV in a mouse model. BMC Infect Dis 2005;5:79-79
   CrossRef | Web of Science | Medline

3. 3

   Weber J, Desai K, Darbyshire J. The development of vaginal microbicides for the prevention of HIV transmission. PLoS Med 2005;2:e142-e142
   CrossRef | Web of Science | Medline

4. 4

   Neurath AR, Strick N, Li Y-Y. Role of seminal plasma in the anti-HIV-1 activity of candidate microbicides. BMC Infect Dis 2006;6:150-150
   CrossRef | Web of Science | Medline

5. 5

   de Witte L, Nabatov A, Pion M, et al. Langerin is a natural barrier to HIV-1 transmission by Langerhans cells. Nat Med 2007;13:367-371
   CrossRef | Web of Science | Medline

To the Editor:

The report that cellulose sulfate did not reduce the risk of HIV acquisition, and in fact increased it in women completing the protocol, is not surprising, given that clinically relevant concentrations of this compound reproducibly increase the in vitro infection rate of sexually transmissible R5-tropic strains of HIV.1 Similar results were reported more than a decade ago for another sulfated polyanion, dextran sulfate, which increased the replication of primary isolates of HIV both in vivo2 and in vitro.3 Unfortunately, detailed titrations, which are essential for detecting enhancement by biphasic compounds such as cellulose and dextran sulfate, have not been published for the viral strains that were prevalent at the trial sites.

Chris Richards, B.S.
Wang Tao, M.D., Ph.D.
Dean Hamer, Ph.D.
National Institutes of Health, Bethesda, MD 20892
deanh@helix.nih.gov

3 References

1. 1

   Tao W, Richards C, Hamer D. Enhancement of HIV infection by cellulose sulfate. AIDS Res Hum Retroviruses 2008;24:925-929
   CrossRef | Web of Science | Medline

2. 2

   Flexner C, Barditch-Crovo PA, Kornhauser DM, et al. Pharmacokinetics, toxicity, and activity of intravenous dextran sulfate in human immunodeficiency virus infection. Antimicrob Agents Chemother 1991;35:2544-2550
   Web of Science | Medline

3. 3

   Meylan PRA, Kornbluth RS, Zbinden I, Richman DD. Influence of host cell type and V3 loop of the surface glycoprotein on susceptibility of human immunodeficiency virus type 1 to polyanion compounds. Antimicrob Agents Chemother 1994;38:2910-2916
   Web of Science | Medline

Author/Editor Response

In response to Neurath: the low pH of a formulation is not enough to inactivate HIV transported by semen (pH of approximately 7.9) unless it is accompanied by a strong acid-buffering capacity. Although the cellulose sulfate and hydroxyethylcellulose-based placebo gels have different pH values, neither has significant buffering capacity. This is reinforced by the lack of anti-HIV activity of the hydroxyethylcellulose placebo (pH of approximately 4.5) in preclinical studies.1 We agree that seminal plasma reduces the antiviral activity of anionic compounds; however, cellulose sulfate S was clinically administered at a concentration (60 mg per milliliter) that is orders of magnitude higher than the seminal plasma–increased median effective concentration reported by Neurath and colleagues.2

Regarding the comments by Richards et al., the statement that clinically relevant concentrations of cellulose sulfate reproducibly increase the in vitro infection rate of R5 tropic strains of HIV (R5-HIV) omits mention of the finding that all other tested concentrations in the data reported by Tao et al.3 were either not effective (<0.3 μg per milliliter) or highly inhibitory (>3 μg per milliliter). Although we do not dispute the reported spike in infectivity between 0.3 and 3.0 μg per milliliter, we question its clinical relevance, given that cellulose sulfate was applied intravaginally at 210 mg per dose. Furthermore, the CONRAD data presented by Tao et al.3 show a reduction in R5-HIV infection between 1.0 and 3.0 μg per milliliter, a disparity in results that cannot be explained by lack of statistical power. Although the results of the intravenous dextran sulfate study should be considered as a possible explanation for our findings, its experimental protocol is considerably different. In addition, cellulose sulfate did not induce a significant increase in macrophage infection in vitro.4

The potential increased risk of infection observed in our per-protocol analysis was driven by results from two sites (Benin and Uganda) where gel was reportedly used 20 times per week on average (9 infections with cellulose sulfate and 1 with placebo). This frequency of use was dramatically higher than the four-times-per-week use reported in South Africa, where there was essentially no evidence of an effect (12 infections with cellulose sulfate and 10 with placebo). Although not conclusive, these findings suggest that a mechanism related to very frequent exposure to cellulose sulfate is a more likely explanation for our results.

Lut Van Damme, M.D.
Doug Taylor, Ph.D.
Family Health International, Arlington, VA 22203
lvandamme@fhi.org

4 References

1. 1

   Tien D, Schnaare RL, Kang F, et al. In vitro and in vivo characterization of a potential universal placebo designed for use in vaginal microbicide clinical trials. AIDS Res Hum Retroviruses 2005;21:845-853
   CrossRef | Web of Science | Medline

2. 2

   Neurath AD, Strick N, Li Y-Y. Role of seminal plasma in the anti-HIV-1 activity of candidate microbicides. BMC Infect Dis 2006;6:150-150
   CrossRef | Web of Science | Medline

3. 3

   Tao W, Richards C, Hamer D. Enhancement of HIV infection by cellulose sulfate. AIDS Res Hum Retroviruses 2008;24:925-929
   CrossRef | Web of Science | Medline

4. 4

   Scordi-Bello IA, Mosoian A, He C, et al. Candidate sulfonated and sulfated topical microbicides: comparison of anti-human immunodeficiency virus activities and mechanisms of action. Antimicrob Agents Chemother 2005;49:3607-3615
   CrossRef | Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Vanessa Pirrone, Brian Wigdahl, Fred C. Krebs. (2011) The rise and fall of polyanionic inhibitors of the human immunodeficiency virus type 1. Antiviral Research 90:3, 168-182
   CrossRef